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Systemic Inflammatory Priming in Normal Pregnancy and Preeclampsia: The Role of Circulating Syncytiotrophoblast Microparticles¹

Sarah J. Germain^*, Gavin P. Sacks^*, Suren R. Soorana, Ian L. Sargent^* and Christopher W. Redman^2,*

^* Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, United Kingdom

Systemic inflammatory responsiveness was studied in normal human pregnancy and its specific inflammatory disorder, pre-eclampsia. Compared with nonpregnancy, monocytes were primed to produce more TNF- throughout normal pregnancy, more IL-12p70 in the first and second trimesters, and more IL-18 in the first trimester only. Intracellular cytokine measurements (TNF- and IL12p70) showed little change by comparison. IFN- production was suppressed in all three trimesters. In pre-eclampsia, IL-18 secretion was increased. Secreted but not intracellular measures of TNF- and IL-12p70 were also further enhanced compared with normal pregnancy. Inhibition of IFN- production was lost and involved both CD56⁺ NK and CD56^– lymphocyte subsets. We determined whether circulating syncytiotrophoblast microparticles (STBM) could contribute to these inflammatory changes. Unbound STBM could be detected in normal pregnancy by the second trimester and increased significantly in the third. They were also bound in vivo to circulating monocytes. Women with pre-eclampsia had significantly more circulating free but not cell-bound STBMs. STBMs prepared by perfusion of normal placental lobules stimulated production of inflammatory cytokines (TNF-, IL12p70, and IL-18 but not IFN-) when cultured with PBMCs from healthy nonpregnant women. Inflammatory priming of PBMCs during pregnancy is confirmed and is established by the first trimester. It is associated with early inhibition of IFN- production. The inflammatory response is enhanced in pre-eclampsia with loss of the IFN- suppression. Circulating STBMs bind to monocytes and stimulate the production of inflammatory cytokines. It is concluded that they are potential contributors to altered systemic inflammatory responsiveness in pregnancy and pre-eclampsia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project was supported by Action Research Grant SP3441 and by the Oxford Radcliffe Hospitals Trust Research and Development Fund.

² Address correspondence and reprint requests to Dr. Christopher W. Redman, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, U.K. E-mail address: christopher.redman{at}obs-gyn.ox.ac.uk

³ Abbreviations used in this paper: HELLP syndrome, acute hemolysis, elevated liver enzymes, and low platelets; STBM, general term for syncytiotrophoblast microparticles; mSTBM, STMsB prepared by a mechanical method; pSTBM, STMsB prepared by perfusion of the maternal surface of the placenta; MsIgG, mouse IgG isotype Ig.

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